Harrison's Neurology in Clinical Medicine, 3rd Edition

CHAPTER 18. APHASIA, MEMORY LOSS, AND OTHER FOCAL CEREBRAL DISORDERS

M.-Marsel Mesulam

The cerebral cortex of the human brain contains approximately 20 billion neurons spread over an area of 2.5 m2. The primary sensory areas provide an obligatory portal for the entry of sensory information into cortical circuitry, and the primary motor areas provide a final common pathway for coordinating complex motor acts. The primary sensory and motor areas constitute 10% of the cerebral cortex. The rest is subsumed by modality-selective, heteromodal, paralimbic, and limbic areas collectively known as the association cortex (Fig. 18-1). The association cortex mediates the integrative processes that subserve cognition, emotion, and behavior. A systematic testing of these mental functions is necessary for the effective clinical assessment of the association cortex and its diseases.

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FIGURE 18-1

Lateral (top) and medial (bottom) views of the cerebral hemispheres. The numbers refer to the Brodmann cyto-architectonic designations. Area 17 corresponds to the primary visual cortex, 41–42 to the primary auditory cortex, 1–3 to the primary somatosensory cortex, and 4 to the primary motor cortex. The rest of the cerebral cortex contains association areas. AG, angular gyrus; B, Broca’s area; CC, corpus callosum; CG, cingulate gyrus; DLPFC, dorsolateral prefrontal cortex; FEF, frontal eye fields (premotor cortex); FG, fusiform gyrus; IPL, inferior parietal lobule; ITG, inferior temporal gyrus; LG, lingual gyrus; MPFC, medial prefrontal cortex; MTG, middle temporal gyrus; OFC, orbitofrontal cortex; PHG, parahippocampal gyrus; PPC, posterior parietal cortex; PSC, peristriate cortex; SC, striate cortex; SMG, supramarginal gyrus; SPL, superior parietal lobule; STG, superior temporal gyrus; STS, superior temporal sulcus; TP, temporopolar cortex; W, Wernicke’s area.

According to current thinking, there are no centers for “hearing words,” “perceiving space,” or “storing memories.” Cognitive and behavioral functions (domains) are coordinated by intersecting large-scale neural networks that contain interconnected cortical and subcortical components. The network approach to higher cerebral function has at least four implications of clinical relevance: (1) A single domain such as language or memory can be disrupted by damage to any one of several areas as long as those areas belong to the same network, (2) damage confined to a single area can give rise to multiple deficits involving the functions of all the networks that intersect in that region, (3) damage to a network component may give rise to minimal or transient deficits if other parts of the network undergo compensatory reorganization, and (4) individual anatomic sites within a network display a relative (but not absolute) specialization for different behavioral aspects of the relevant function. Five anatomically defined large-scale networks are most relevant to clinical practice: (1) a perisylvian network for language, (2) a parietofrontal network for spatial cognition, (3) an occipitotemporal network for face and object recognition, (4) a limbic network for retentive memory, and (5) a prefrontal network for cognitive and behavioral control.

THE LEFT PERISYLVIAN NETWORK FOR LANGUAGE: APHASIAS AND RELATED CONDITIONS

Language allows the communication and elaboration of thoughts and experiences by linking them to arbitrary symbols known as words. The neural substrate of language is composed of a distributed network centered in the perisylvian region of the left hemisphere. The posterior pole of this network is located at the temporoparietal junction and includes a region known as Wernicke’s area. An essential function of Wernicke’s area is to transform sensory inputs into their neural word representations so that they can establish the distributed associations that give a word its meaning. The anterior pole of the language network is located in the inferior frontal gyrus and includes a region known as Broca’s area. An essential function of this area is to transform neural word representations into their articulatory sequences so that the words can be uttered in the form of spoken language. The sequencing function of Broca’s area also appears to involve the ordering of words into sentences that contain a meaning-appropriate syntax(grammar). Wernicke’s and Broca’s areas are interconnected with each other and with additional perisylvian, temporal, prefrontal, and posterior parietal regions, making up a neural network that subserves the various aspects of language function. Damage to any one of these components or to their interconnections can give rise to language disturbances (aphasia). Aphasia should be diagnosed only when there are deficits in the formal aspects of language, such as naming, word choice, comprehension, spelling, and syntax. Dysarthria and mutism do not by themselves lead to a diagnosis of aphasia. The language network shows a left hemisphere dominance pattern in the vast majority of the population. In approximately 90% of right-handers and 60% of left-handers, aphasia occurs only after lesions of the left hemisphere. In some individuals no hemispheric dominance for language can be discerned, and in some others (including a small minority of right handers) there is a right hemisphere dominance for language. A language disturbance that occurs after a right hemisphere lesion in a right hander is called crossed aphasia.

CLINICAL EXAMINATION

The clinical examination of language should include the assessment of naming, spontaneous speech, comprehension, repetition, reading, and writing. A deficit of naming (anomia) is the single most common finding in aphasic patients. When asked to name a common object (pencil or wristwatch), the patient may fail to come up with the appropriate word, may provide a circumlocutious description of the object (“the thing for writing”), or may come up with the wrong word (paraphasia). If the patient offers an incorrect but related word (“pen” for “pencil”), the naming error is known as a semantic paraphasia; if the word approximates the correct answer but is phonetically inaccurate (“plentil” for “pencil”), it is known as a phonemic paraphasia. Asking the patient to name body parts, geometric shapes, and component parts of objects (lapel of coat, cap of pen) can elicit mild forms of anomia in patients who otherwise can name common objects. In most anomias, the patient cannot retrieve the appropriate name when shown an object but can point to the appropriate object when the name is provided by the examiner. This is known as a one-way (or retrieval-based) naming deficit. A two-way naming deficit exists if the patient can neither provide nor recognize the correct name, indicating the likely presence of a comprehension impairment for the word. Spontaneous speech is described as “fluent” if it maintains appropriate output volume, phrase length, and melody or as “nonfluent” if it is sparse and halting and average utterance length is below four words. The examiner also should note if the speech is paraphasic or circumlocutious; if it shows a relative paucity of substantive nouns and action verbs versus function words (prepositions, conjunctions); and if word order, tenses, suffixes, prefixes, plurals, and possessives are appropriate. Comprehension can be tested by assessing the patient’s ability to follow conversation, asking yes-no questions (“Can a dog fly?”, “Does it snow in summer?”) or asking the patient to point to appropriate objects (“Where is the source of illumination in this room?”). Statements with embedded clauses or a passive voice construction (“If a tiger is eaten by a lion, which animal stays alive?”) help assess the ability to comprehend complex syntactic structure. Commands to close or open the eyes, stand up, sit down, or roll over should not be used to assess overall comprehension since appropriate responses aimed at such axial movements can be preserved in patients who otherwise have profound comprehension deficits.

Repetition is assessed by asking the patient to repeat single words, short sentences, or strings of words such as “No ifs, ands, or buts.” The testing of repetition with tongue twisters such as “hippopotamus” and “Irish constabulary” provides a better assessment of dysarthria and pallilalia than of aphasia. Aphasic patients who have little difficulty with tongue twisters may have a particularly hard time repeating a string of function words. It is important to make sure that the number of words does not exceed the patient’s attention span. Otherwise, the failure of repetition becomes a reflection of the narrowed attention span rather than an indication of an aphasic deficit. Reading should be assessed for deficits in reading aloud as well as comprehension. Writing is assessed for spelling errors, word order, and grammar. Alexiadescribes an inability to either read aloud or comprehend single words and simple sentences; agraphia (or dysgraphia) is used to describe an acquired deficit in the spelling or grammar of written language.

The correspondence between individual deficits of language function and lesion location does not display a rigid one-to-one relationship and should be conceptualized within the context of the distributed network model. Nonetheless, the classification of aphasias into specific clinical syndromes helps determine the most likely anatomic distribution of the underlying neurologic disease and has implications for etiology and prognosis (Table 18-1). The syndromes listed in Table 18-1 are most applicable to aphasias caused by cerebrovascular accidents (CVAs). They can be divided into “central” syndromes, which result from damage to the two epicenters of the language network (Broca’s and Wernicke’s areas), and “disconnection” syndromes, which arise from lesions that interrupt the functional connectivity of those centers with each other and with the other components of the language network. The syndromes outlined next are idealizations; pure syndromes occur rarely.

TABLE 18-1

CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS

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Wernicke’s aphasia

Comprehension is impaired for spoken and written language, for single words as well as sentences. Language output is fluent but is highly paraphasic and circumlocutious. The tendency for paraphasic errors may be so pronounced that it leads to strings of neologisms, which form the basis of what is known as “jargon aphasia.” Speech contains large numbers of function words (e.g., prepositions, conjunctions) but few substantive nouns or verbs that refer to specific actions. The output is therefore voluminous but uninformative. For example, a patient attempts to describe how his wife accidentally threw away something important, perhaps his dentures: “We don’t need it anymore, she says. And with it when that was downstairs was my teeth-tick…a… den…dentith…my dentist. And they happened to be in that bag…see? How could this have happened? How could a thing like this happen…So she says we won’t need it anymore…I didn’t think we’d use it. And now if I have any problems anybody coming a month from now, 4 months from now, or 6 months from now, I have a new dentist. Where my two…two little pieces of dentist that I use…that I…all gone. If she throws the whole thing away…visit some friends of hers and she can’t throw them away.”

Gestures and pantomime do not improve communication. The patient does not seem to realize that his or her language is incomprehensible and may appear angry and impatient when the examiner fails to decipher the meaning of a severely paraphasic statement. In some patients this type of aphasia can be associated with severe agitation and paranoid behaviors. One area of comprehension that may be preserved is the ability to follow commands aimed at axial musculature. The dissociation between the failure to understand simple questions (“What is your name?”) in a patient who rapidly closes his or her eyes, sits up, or rolls over when asked to do so is characteristic of Wernicke’s aphasia and helps differentiate it from deafness, psychiatric disease, or malingering. Patients with Wernicke’s aphasia cannot express their thoughts in meaning-appropriate words and cannot decode the meaning of words in any modality of input. This aphasia therefore has expressive as well as receptive components. Repetition, naming, reading, and writing also are impaired.

The lesion site most commonly associated with Wernicke’s aphasia is the posterior portion of the language network and tends to involve at least parts of Wernicke’s area. An embolus to the inferior division of the middle cerebral artery, to the posterior temporal or angular branches in particular, is the most common etiology. Intracerebral hemorrhage, severe head trauma, and neoplasm are other causes. A coexisting right hemianopia or superior quadrantanopia is common and mild right nasolabial flattening may be found, but otherwise the examination is often unrevealing. The paraphasic, neologistic speech in an agitated patient with an otherwise unremarkable neurologic examination may lead to the suspicion of a primary psychiatric disorder such as schizophrenia or mania, but the other components characteristic of acquired aphasia and the absence of prior psychiatric disease usually settle the issue. Some patients with Wernicke’s aphasia due to intracerebral hemorrhage or head trauma may improve as the hemorrhage or the injury heals. In most other patients, prognosis for recovery of language function is guarded.

Broca’s aphasia

Speech is nonfluent, labored, interrupted by many word-finding pauses, and usually dysarthric. It is impoverished in function words but enriched in meaning-appropriate nouns and verbs. Abnormal word order and the inappropriate deployment of bound morphemes (word endings used to denote tenses, possessives, or plurals) lead to a characteristic agrammatism. Speech is telegraphic and pithy but quite informative. In the following passage, a patient with Broca’s aphasia describes his medical history: “I see…the dotor, dotor sent me… Bosson. Go to hospital. Dotor…kept me beside. Two, tee days, doctor send me home.”

Output may be reduced to a grunt or single word (“yes” or “no”), which is emitted with different intonations in an attempt to express approval or disapproval. In addition to fluency, naming and repetition are impaired. Comprehension of spoken language is intact except for syntactically difficult sentences with a passive voice structure or embedded clauses. Reading comprehension also is preserved with the occasional exception of a specific inability to read small grammatical words such as conjunctions and pronouns. The last two features indicate that Broca’s aphasia is not just an “expressive” or “motor” disorder and that it also may involve a comprehension deficit for function words and syntax. Patients with Broca’s aphasia can be tearful, easily frustrated, and profoundly depressed. Insight into their condition is preserved, in contrast to Wernicke’s aphasia. Even when spontaneous speech is severely dysarthric, the patient may be able to display a relatively normal articulation of words when singing. This dissociation has been used to develop specific therapeutic approaches (melodic intonation therapy) for Broca’s aphasia. Additional neurologic deficits usually include right facial weakness, hemiparesis or hemiplegia, and a buccofacial apraxia characterized by an inability to carry out motor commands involving oropharyngeal and facial musculature (e.g., patients are unable to demonstrate how to blow out a match or suck through a straw). Visual fields are intact. The cause is most often infarction of Broca’s area (the inferior frontal convolution; “B” in Fig. 18-1) and surrounding anterior perisylvian and insular cortex due to occlusion of the superior division of the middle cerebral artery. Mass lesions, including tumor, intracerebral hemorrhage, and abscess, also may be responsible. Small lesions confined to the posterior part of Broca’s area may lead to a nonaphasic and often reversible deficit of speech articulation that usually is accompanied by mild right facial weakness. When the cause of Broca’s aphasia is stroke, recovery of language function generally peaks within 2 to 6 months, after which time further progress is limited.

Global aphasia

Speech output is nonfluent, and comprehension of spoken language is severely impaired. Naming, repetition, reading, and writing also are impaired. This syndrome represents the combined dysfunction of Broca’s and Wernicke’s areas and usually results from strokes that involve the entire middle cerebral artery distribution in the left hemisphere. Most patients are initially mute or say a few words, such as “hi” or “yes.” Related signs include right hemiplegia, hemisensory loss, and homonymous hemianopia. Occasionally, a patient with a lesion in Wernicke’s area will present with a global aphasia that soon resolves into Wernicke’s aphasia.

Conduction aphasia

Speech output is fluent but paraphasic, comprehension of spoken language is intact, and repetition is severely impaired. Naming and writing also are impaired. Reading aloud is impaired, but reading comprehension is preserved. The lesion sites spare Broca’s and Wernicke’s areas but may induce a functional disconnection between the two so that neural word representations formed in Wernicke’s area and adjacent regions cannot be conveyed to Broca’s area for assembly into corresponding articulatory patterns. Occasionally, a Wernicke’s area lesion gives rise to a transient Wernicke’s aphasia that rapidly resolves into a conduction aphasia. The paraphasic output in conduction aphasia interferes with the ability to express meaning, but this deficit is not nearly as severe as the one displayed by patients with Wernicke’s aphasia. Associated neurologic signs in conduction aphasia vary according to the primary lesion site.

Nonfluent transcortical aphasia (transcortical motor aphasia)

The features are similar to those of Broca’s aphasia, but repetition is intact and agrammatism may be less pronounced. The neurologic examination may be otherwise intact, but a right hemiparesis also can exist. The lesion site disconnects the intact language network from prefrontal areas of the brain and usually involves the anterior watershed zone between anterior and middle cerebral artery territories or the supplementary motor cortex in the territory of the anterior cerebral artery.

Fluent transcortical aphasia (transcortical sensory aphasia)

Clinical features are similar to those of Wernicke’s aphasia, but repetition is intact. The lesion site disconnects the intact core of the language network from other temporoparietal association areas. Associated neurologic findings may include hemianopia. Cerebrovascular lesions (e.g., infarctions in the posterior watershed zone) and neoplasms that involve the temporoparietal cortex posterior to Wernicke’s area are the most common causes.

Isolation aphasia

This rare syndrome represents a combination of the two transcortical aphasias. Comprehension is severely impaired, and there is no purposeful speech output. The patient may parrot fragments of heard conversations (echolalia), indicating that the neural mechanisms for repetition are at least partially intact. This condition represents the pathologic function of the language network when it is isolated from other regions of the brain. Broca’s and Wernicke’s areas tend to be spared, but there is damage to the surrounding frontal, parietal, and temporal cortex. Lesions are patchy and can be associated with anoxia, carbon monoxide poisoning, or complete watershed zone infarctions.

Anomic aphasia

This form of aphasia may be considered the “minimal dysfunction” syndrome of the language network. Articulation, comprehension, and repetition are intact, but confrontation naming, word finding, and spelling are impaired. Speech is enriched in function words but impoverished in substantive nouns and verbs denoting specific actions. Language output is fluent but paraphasic, circumlocutious, and uninformative. Fluency may be interrupted by word-finding hesitations. The lesion sites can be anywhere within the left hemisphere language network, including the middle and inferior temporal gyri. Anomic aphasia is the single most common language disturbance seen in head trauma, metabolic encephalopathy, and Alzheimer’s disease.

Pure word deafness

The most common causes are either bilateral or left-sided middle cerebral artery (MCA) strokes affecting the superior temporal gyrus. The net effect of the underlying lesion is to interrupt the flow of information from the auditory association cortex to Wernicke’s area. Patients have no difficulty understanding written language and can express themselves well in spoken or written language. They have no difficulty interpreting and reacting to environmental sounds since primary auditory cortex and subcortical auditory relays are intact. Since auditory information cannot be conveyed to the language network, however, it cannot be decoded into neural word representations, and the patient reacts to speech as if it were in an alien tongue that cannot be deciphered. Patients cannot repeat spoken language but have no difficulty naming objects. In time, patients with pure word deafness teach themselves lipreading and may appear to have improved. There may be no additional neurologic findings, but agitated paranoid reactions are common in the acute stages. Cerebrovascular lesions are the most common cause.

Pure alexia without agraphia

This is the visual equivalent of pure word deafness. The lesions (usually a combination of damage to the left occipital cortex and to a posterior sector of the corpus callosum—the splenium) interrupt the flow of visual input into the language network. There is usually a right hemianopia, but the core language network remains unaffected. The patient can understand and produce spoken language, name objects in the left visual hemifield, repeat, and write. However, the patient acts as if illiterate when asked to read even the simplest sentence because the visual information from the written words (presented to the intact left visual hemifield) cannot reach the language network. Objects in the left hemifield may be named accurately because they activate nonvisual associations in the right hemisphere, which in turn can access the language network through transcallosal pathways anterior to the splenium. Patients with this syndrome also may lose the ability to name colors, although they can match colors. This is known as a color anomia. The most common etiology of pure alexia is a vascular lesion in the territory of the posterior cerebral artery or an infiltrating neoplasm in the left occipital cortex that involves the optic radiations as well as the crossing fibers of the splenium. Since the posterior cerebral artery also supplies medial temporal components of the limbic system, a patient with pure alexia also may experience an amnesia, but this is usually transient because the limbic lesion is unilateral.

Aphemia

There is an acute onset of severely impaired fluency (often mutism), which cannot be accounted for by corticobulbar, cerebellar, or extrapyramidal dysfunction. Recovery is the rule and involves an intermediate stage of hoarse whispering. Writing, reading, and comprehension are intact, and so this is not a true aphasic syndrome. Partial lesions of Broca’s area or subcortical lesions that undercut its connections with other parts of the brain may be present. Occasionally, the lesion site is on the medial aspects of the frontal lobes and may involve the supplementary motor cortex of the left hemisphere.

Apraxia

This generic term designates a complex motor deficit that cannot be attributed to pyramidal, extrapyramidal, cerebellar, or sensory dysfunction and that does not arise from the patient’s failure to understand the nature of the task. The form that is encountered most frequently in clinical practice is known as ideomotor apraxia. Commands to perform a specific motor act (“cough,” “blow out a match”) or pantomime the use of a common tool (a comb, hammer, straw, or toothbrush) in the absence of the real object cannot be followed. The patient’s ability to comprehend the command is ascertained by demonstrating multiple movements and establishing that the correct one can be recognized. Some patients with this type of apraxia can imitate the appropriate movement (when it is demonstrated by the examiner) and show no impairment when handed the real object, indicating that the sensorimotor mechanisms necessary for the movement are intact. Some forms of ideomotor apraxia represent a disconnection of the language network from pyramidal motor systems: commands to execute complex movements are understood but cannot be conveyed to the appropriate motor areas even though the relevant motor mechanisms are intact. Buccofacial apraxia involves apraxic deficits in movements of the face and mouth. Limb apraxia encompasses apraxic deficits in movements of the arms and legs. Ideomotor apraxia almost always is caused by lesions in the left hemisphere and is commonly associated with aphasic syndromes, especially Broca’s aphasia and conduction aphasia. Its presence cannot be ascertained in patients with language comprehension deficits. The ability to follow commands aimed at axial musculature (“close the eyes,” “stand up”) is subserved by different pathways and may be intact in otherwise severely aphasic and apraxic patients. Since the handling of real objects is not impaired, ideomotor apraxia by itself causes no major limitation of daily living activities. Patients with lesions of the anterior corpus callosum can display ideomotor apraxia confined to the left side of the body, a sign known as sympathetic dyspraxia. A severe form of sympathetic dyspraxia known as the alien hand syndrome is characterized by additional features of motor disinhibition on the left hand.

Ideational apraxia refers to a deficit in the execution of a goal-directed sequence of movements in patients who have no difficulty executing the individual components of the sequence. For example, when the patient is asked to pick up a pen and write, the sequence of uncapping the pen, placing the cap at the opposite end, turning the point toward the writing surface, and writing may be disrupted, and the patient may be seen trying to write with the wrong end of the pen or even with the removed cap. These motor sequencing problems usually are seen in the context of confusional states and dementias rather than focal lesions associated with aphasic conditions. Limb-kinetic apraxia involves a clumsiness in the actual use of tools that cannot be attributed to sensory, pyramidal, extra-pyramidal, or cerebellar dysfunction. This condition can emerge in the context of focal premotor cortex lesions or corticobasal degeneration.

Gerstmann’s syndrome

The combination of acalculia (impairment of simple arithmetic), dysgraphia (impaired writing), finger anomia (an inability to name individual fingers such as the index and thumb), and right-left confusion(an inability to tell whether a hand, foot, or arm of the patient or examiner is on the right or left side of the body) is known as Gerstmann’s syndrome. In making this diagnosis it is important to establish that the finger and left-right naming deficits are not part of a more generalized anomia and that the patient is not otherwise aphasic. When Gerstmann’s syndrome is seen in isolation, it is commonly associated with damage to the inferior parietal lobule (especially the angular gyrus) in the left hemisphere.

Aprosodia

Variations of melodic stress and intonation influence the meaning and impact of spoken language. For example, the two statements “He is clever.” and “He is clever?” contain an identical word choice and syntax but convey vastly different messages because of differences in the intonation and stress with which the statements are uttered. This aspect of language is known as prosody. Damage to perisylvian areas in the right hemisphere can interfere with speech prosody and can lead to syndromes of aprosodia. Damage to right hemisphere regions corresponding to Wernicke’s area can selectively impair decoding of speech prosody, whereas damage to right hemisphere regions corresponding to Broca’s area yields a greater impairment in the ability to introduce meaning-appropriate prosody into spoken language. The latter deficit is the most common type of aprosodia identified in clinical practice; the patient produces grammatically correct language with accurate word choice, but the statements are uttered in a monotone that interferes with the ability to convey the intended stress and affect. Patients with this type of aprosodia give the mistaken impression of being depressed or indifferent.

Subcortical aphasia

Damage to subcortical components of the language network (e.g., the striatum and thalamus of the left hemisphere) also can lead to aphasia. The resulting syndromes contain combinations of deficits in the various aspects of language but rarely fit the specific patterns described in Table 18-1. In a patient with a CVA, an anomic aphasia accompanied by dysarthria or a fluent aphasia with hemiparesis should raise the suspicion of a subcortical lesion site.

Progressive aphasias

Aphasias caused by cerebrovascular accidents start suddenly and display maximal deficits at the onset. The underlying lesion is relatively circumscribed and is associated with a total loss of neural function in at least part of the lesion site. These are the “classic” aphasias described earlier in this chapter. Aphasias caused by neurodegenerative diseases have an insidious onset and a relentless progression so that the symptomatology changes over time. Since the neuronal loss within the areas encompassed by the neurodegeneration is partial and since it tends to include multiple components of the language network, the clinico-anatomic patterns are different from those described in Table 18-1.

Image Clinical presentation and diagnosis of primary progressive aphasia (PPA)

When a neurodegenerative disease selectively undermines language function, a clinical diagnosis of PPA is made. A patient with PPA comes to medical attention because of word-finding difficulties, abnormal speech patterns, word-comprehension impairments, or spelling errors of recent onset. PPA is diagnosed when other mental faculties, such as memory for daily events, visuo-spatial skills (assessed by tests of drawing and face recognition), and comportment (assessed by history obtained from a third party), remain relatively intact; when language is the major area of dysfunction for the first few years of the disease; and when structural brain imaging does not reveal a specific lesion, other than atrophy, that accounts for the language deficit. Impairments in other cognitive functions may emerge eventually, but the language dysfunction remains the most salient feature and deteriorates most rapidly throughout the illness.

Image Language in PPA

The language impairment in PPA varies from patient to patient. Some patients cannot find the right words to express thoughts; others cannot understand the meaning of heard or seen words; still others cannot name objects in the environment. The language impairment can be fluent (that is, with normal articulation, flow, and number of words per utterance) or nonfluent. The single most common sign of primary progressive aphasia is an inability to come up with the right word during conversation and/or an inability to name objects shown by the examiner (anomia). Distinct forms of agrammatism and/or word comprehension deficits also can arise. The agrammatism consists of inappropriate word order and misuse of small grammatical words. Comprehension deficits, if present, start with an occasional inability to understand single low-frequency words and gradually progress to encompass the comprehension of conversational speech.

The impairments of syntax, comprehension, naming, or writing in PPA form slightly different patterns from those seen in CVA-caused aphasias. Three subtypes of PPA can be recognized: an agrammatic variant characterized by poor fluency and impaired grammar, a semantic variant characterized by preserved fluency and syntax but poor single word comprehension, and a logopenic variant characterized by preserved syntax and comprehension but frequent word-finding pauses during spontaneous speech. The agrammatic variant also is known as progressive nonfluent aphasia and displays similarities to Broca’s aphasia. However, dysarthria is usually absent. The semantic variant of PPA displays similarities to Wernicke’s aphasia, but the comprehension difficulty tends to be most profound for single words denoting concrete objects.

Image Pathophysiology

The three variants of PPA display overlapping distributions of neuronal loss, but the agrammatic variant is most closely associated with atrophy in the anterior parts of the language network (where Broca’s area is located), the semantic variant with atrophy in the anterior temporal components of the language network, and the logopenic variant with atrophy in the temporoparietal component of the language network. The abnormalities may remain confined to the left hemisphere perisylvian and anterior temporal cortices initially, but gradual deterioration in PPA leads to a loss of syndromic specificity as the disease progresses.

Image Neuropathology

In the majority of PPA cases, the neuropathology falls within the family of frontotemporal lobar degenerations (FTLDs) and displays various combinations of focal neuronal loss, gliosis, tau-positive inclusions including Pick bodies, and tau-negative TDP-43 inclusions. Familial forms of PPA with TDP-43 inclusions recently were linked to mutations of the progranulin gene on chromosome 17. The agrammatic variant most frequently is associated with tauopathy, whereas the semantic variant is most closely associated with TDP-43 inclusions. Alzheimer’s pathology is seen most frequently in the logopenic variant. The clinical subtyping of PPA thus may help predict the nature of the underlying neuropathology. The intriguing possibility has been raised that a personal or family history of dyslexia may be a risk factor for primary progressive aphasia, at least in some patients, suggesting that this disease may arise on a background of genetic or developmental vulnerability that affects language-related areas of the brain.

THE PARIETOFRONTAL NETWORK FOR SPATIAL ORIENTATION: NEGLECT AND RELATED CONDITIONS

HEMISPATIAL NEGLECT

Adaptive orientation to significant events within the extrapersonal space is subserved by a large-scale network containing three major cortical components. The cingulate cortex provides access to a motivational mapping of the extrapersonal space, the posterior parietal cortex to a sensorimotor representation of salient extrapersonal events, and the frontal eye fields to motor strategies for attentional behaviors (Fig. 18-2). Subcortical components of this network include the striatum and the thalamus. Contralesional hemispatial neglect represents one outcome of damage to any of the cortical or sub-cortical components of this network. The traditional view that hemispatial neglect always denotes a parietal lobe lesion is inaccurate. In keeping with this anatomic organization, the clinical manifestations of neglect display three behavioral components: sensory events (or their mental representations) within the neglected hemispace have a lesser impact on overall awareness, there is a paucity of exploratory and orienting acts directed toward the neglected hemispace, and the patient behaves as if the neglected hemispace were motivationally devalued.

Image

FIGURE 18-2

Functional magnetic resonance imaging of language and spatial attention in neurologically intact subjects. The red and black areas show regions of task-related significant activation. (Top) The subjects were asked to determine if two words were synonymous. This language task led to the simultaneous activation of the two epicenters of the language network, Broca’s area (B) and Wernicke’s area (W). The activations are exclusively in the left hemisphere. (Bottom) The subjects were asked to shift spatial attention to a peripheral target. This task led to the simultaneous activation of the three epicenters of the attentional network: the posterior parietal cortex (P), the frontal eye fields (F), and the cingulate gyrus (CG). The activations are predominantly in the right hemisphere. (Courtesy of Darren Gitelman, MD; with permission.)

According to one model of spatial cognition, the right hemisphere directs attention within the entire extrapersonal space, whereas the left hemisphere directs attention mostly within the contralateral right hemispace. Consequently, unilateral left hemisphere lesions do not give rise to much contralesional neglect since the global attentional mechanisms of the right hemisphere can compensate for the loss of the contralaterally directed attentional functions of the left hemisphere. Unilateral right hemisphere lesions, however, give rise to severe contralesional left hemispatial neglect because the unaffected left hemisphere does not contain ipsilateral attentional mechanisms. This model is consistent with clinical experience, which shows that contralesional neglect is more common, severe, and lasting after damage to the right hemisphere than after damage to the left hemisphere. Severe neglect for the right hemispace is rare, even in left-handers with left hemisphere lesions.

Clinical examination

Patients with severe neglect may fail to dress, shave, or groom the left side of the body; fail to eat food placed on the left side of the tray; and fail to read the left half of sentences. When the examiner draws a large circle (12 to 15 cm [5 to 6 in.] in diameter) and asks the patient to place the numbers 1 to 12 as if the circle represented the face of a clock, there is a tendency to crowd the numbers on the right side and leave the left side empty. When asked to copy a simple line drawing, the patient fails to copy detail on the left, and when the patient is asked to write, there is a tendency to leave an unusually wide margin on the left.

Two bedside tests that are useful in assessing neglect are simultaneous bilateral stimulation and visual target cancellation. In the former, the examiner provides either unilateral or simultaneous bilateral stimulation in the visual, auditory, and tactile modalities. After right hemisphere injury, patients who have no difficulty detecting unilateral stimuli on either side experience the bilaterally presented stimulus as coming only from the right. This phenomenon is known as extinction and is a manifestation of the sensory-representational aspect of hemispatial neglect. In the target detection task, targets (e.g., A’s) are interspersed with foils (e.g., other letters of the alphabet) on a 21.5- to 28.0-cm (8.5 to 11 in.) sheet of paper, and the patient is asked to circle all the targets. A failure to detect targets on the left is a manifestation of the exploratory deficit in hemispatial neglect (Fig. 18-3A). Hemianopia is not by itself sufficient to cause the target detection failure since the patient is free to turn the head and eyes to the left. Target detection failures therefore reflect a distortion of spatial attention, not just of sensory input. The normal tendency in target detection tasks is to start from the left upper quadrant and move systematically in horizontal or vertical sweeps. Some patients show a tendency to start the process from the right and proceed in a haphazard fashion. This represents a subtle manifestation of left neglect even if the patient eventually manages to detect all the appropriate targets. Some patients with neglect also may deny the existence of hemiparesis and may even deny ownership of the paralyzed limb, a condition known as anosognosia.

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FIGURE 18-3

A. A 47-year-old man with a large frontoparietal lesion in the right hemisphere was asked to circle all the A’s. Only targets on the right are circled. This is a manifestation of left hemispatial neglect. B. A 70-year-old woman with a 2-year history of degenerative dementia was able to circle most of the small targets but ignored the larger ones. This is a manifestation of simultanagnosia.

BÁLINT’S SYNDROME, SIMULTANAGNOSIA, DRESSING APRAXIA, AND CONSTRUCTION APRAXIA

Bilateral involvement of the network for spatial attention, especially its parietal components, leads to a state of severe spatial disorientation known as Bálint’s syndrome. Bálint’s syndrome involves deficits in the orderly visuomotor scanning of the environment (oculomotor apraxia) and in accurate manual reaching toward visual targets (optic ataxia). The third and most dramatic component of Bálint’s syndrome is known as simultanagnosia and reflects an inability to integrate visual information in the center of gaze with more peripheral information. The patient gets stuck on the detail that falls in the center of gaze without attempting to scan the visual environment for additional information. A patient with simultanagnosia “misses the forest for the trees.” Complex visual scenes cannot be grasped in their entirety, leading to severe limitations in the visual identification of objects and scenes. For example, a patient who is shown a table lamp and asked to name the object may look at its circular base and call it an ashtray. Some patients with simultanagnosia report that objects they look at may vanish suddenly, probably indicating an inability to look back at the original point of gaze after brief saccadic displacements. Movement and distracting stimuli greatly exacerbate the difficulties of visual perception. Simultanagnosia sometimes can occur without the other two components of Bálint’s syndrome.

A modification of the letter cancellation task described earlier can be used for the bedside diagnosis of simultanagnosia. In this modification, some of the targets (e.g., A’s) are made to be much larger than the others (7.5 to 10 cm vs. 2.5 cm [3 to 4 in. vs. 1 in.] in height), and all targets are embedded among foils. Patients with simultanagnosia display a counterintuitive but characteristic tendency to miss the larger targets (Fig. 18-3B). This occurs because the information needed for the identification of the larger targets cannot be confined to the immediate line of gaze and requires the integration of visual information across a more extensive field of view. The greater difficulty in the detection of the larger targets also indicates that poor acuity is not responsible for the impairment of visual function and that the problem is central rather than peripheral.

Another manifestation of bilateral (or right-sided) dorsal parietal lobe lesions is dressing apraxia. A patient with this condition is unable to align the body axis with the axis of the garment and can be seen struggling as he or she holds a coat from its bottom or extends his or her arm into a fold of the garment rather than into its sleeve. Lesions that involve the posterior parietal cortex also lead to severe difficulties in copying simple line drawings. This is known as a construction apraxia and is much more severe if the lesion is in the right hemisphere. In some patients with right hemisphere lesions, the drawing difficulties are confined to the left side of the figure and represent a manifestation of hemispatial neglect; in others, there is a more universal deficit in reproducing contours and three-dimensional perspective. Dressing apraxia and construction apraxia represent special instances of a more general disturbance in spatial orientation.

Causes of spatial disorientation

Cerebrovascular lesions and neoplasms in the right hemisphere are the most common causes of hemispatial neglect. Depending on the site of the lesion, a patient with neglect also may have hemiparesis, hemihypesthesia, and hemianopia on the left, but these are not invariant findings. The majority of these patients display considerable improvement of hemispatial neglect, usually within the first several weeks. Bálint’s syndrome results from bilateral dorsal parietal lesions; common settings include watershed infarction between the middle and posterior cerebral artery territories, hypoglycemia, and sagittal sinus thrombosis.

A progressive form of spatial disorientation known as the posterior cortical atrophy syndrome most commonly represents a variant of Alzheimer’s disease with unusual concentrations of neurofibrillary degeneration in the parieto-occipital cortex and the superior colliculus. The patient displays a progressive Bálint’s syndrome, usually accompanied by dressing and construction apraxia. Corticobasal degeneration, a type of FTLD with abnormal tau inclusions, can have an asymmetric distribution. When the atrophy shows a predilection for the right cerebral hemisphere, a progressive left hemineglect syndrome emerges on a background of left-sided extrapyramidal dysfunction.

THE OCCIPITOTEMPORAL NETWORK FOR FACE AND OBJECT RECOGNITION: PROSOPAGNOSIA AND OBJECT AGNOSIA

Perceptual information about faces and objects initially is encoded in primary (striate) visual cortex and adjacent (upstream) peristriate visual association areas. This information subsequently is relayed first to the downstream visual association areas of occipitotemporal cortex and then to other heteromodal and paralimbic areas of the cerebral cortex. Bilateral lesions in the fusiform and lingual gyri of the occipitotemporal cortex disrupt this process and interfere with the ability of otherwise intact perceptual information to activate the distributed multimodal associations that lead to the recognition of faces and objects. The resultant face and object recognition deficits are known as associative prosopagnosia and visual object agnosia.

A patient with prosopagnosia cannot recognize familiar faces, including, sometimes, the reflection of his or her own face in the mirror. This is not a perceptual deficit since prosopagnosic patients easily can tell whether two faces are identical. Furthermore, a prosopagnosic patient who cannot recognize a familiar face by visual inspection alone can use auditory cues to reach appropriate recognition if allowed to listen to the person’s voice. The deficit in prosopagnosia is therefore modality-specific and reflects the existence of a lesion that prevents the activation of otherwise intact multimodal templates by relevant visual input. The deficit in prosopagnosia is not limited to the recognition of faces but also can extend to the recognition of individual members of larger generic object groups. For example, prosopagnosic patients characteristically have no difficulty with the generic identification of a face as a face or a car as a car, but they cannot recognize the identity of an individual face or the make of an individual car. This reflects a visual recognition deficit for proprietary features that characterize individual members of an object class. When recognition problems become more generalized and extend to the generic identification of common objects, the condition is known as visual object agnosia. In contrast to prosopagnosic patients, those with object agnosia cannot recognize a face as a face or a car as a car. It is important to distinguish visual object agnosia from anomia. A patient with anomia cannot name the object but can describe its use. In contrast, a patient with visual agnosia is unable either to name a visually presented object or to describe its use. Face and object recognition disorders also can result from the simultanagnosia of Bálint’s syndrome, in which case they are known as apperceptiveagnosias as opposed to the associative agnosias that result from inferior temporal lobe lesions.

CAUSES

The characteristic lesions in prosopagnosia and visual object agnosia consist of bilateral infarctions in the territory of the posterior cerebral arteries. Associated deficits can include visual field defects (especially superior quadrantanopias) and a centrally based color blindness known as achromatopsia. Rarely, the responsible lesion is unilateral. In such cases, prosopagnosia is associated with lesions in the right hemisphere, and object agnosia with lesions in the left. Degenerative diseases of anterior and inferior temporal cortex can cause progressive associative prosopagnosia and object agnosia. The combination of progressive associative agnosia and a fluent aphasia is known as semantic dementia and usually is caused by FTLD with TDP-43 inclusions. Patients with semantic dementia fail to recognize faces and objects and cannot understand the meaning of words denoting objects.

THE LIMBIC NETWORK FOR EPISODIC MEMORY: AMNESIAS

Limbic and paralimbic areas (such as the hippocampus, amygdala, and entorhinal cortex), the anterior and medial nuclei of the thalamus, the medial and basal parts of the striatum, and the hypothalamus collectively constitute a distributed network known as the limbic system. The behavioral affiliations of this network include the coordination of emotion, motivation, autonomic tone, and endocrine function. An additional area of specialization for the limbic network and the one that is of most relevance to clinical practice is that of declarative (conscious) memory for recent episodes and experiences. A disturbance in this function is known as an amnestic state. In the absence of deficits in motivation, attention, language, or visuospatial function, the clinical diagnosis of a persistent global amnestic state is always associated with bilateral damage to the limbic network, usually within the hippocampo-entorhinal complex or the thalamus.

Although the limbic network is the site of damage for amnestic states, it is almost certainly not the storage site for memories. Memories are stored in widely distributed form throughout the cerebral cortex. The role attributed to the limbic network is to bind these distributed fragments into coherent events and experiences that can sustain conscious recall. Damage to the limbic network does not necessarily destroy memories but interferes with their conscious (declarative) recall in coherent form. The individual fragments of information remain preserved despite the limbic lesions and can sustain what is known as implicit memory. For example, patients with amnestic states can acquire new motor or perceptual skills even though they may have no conscious knowledge of the experiences that led to the acquisition of these skills.

The memory disturbance in the amnestic state is multimodal and includes retrograde and anterograde components. The retrograde amnesia involves an inability to recall experiences that occurred before the onset of the amnestic state. Relatively recent events are more vulnerable to retrograde amnesia than are more remote and more extensively consolidated events. A patient who comes to the emergency room complaining that he cannot remember his or her identity but can remember the events of the previous day almost certainly does not have a neurologic cause of memory disturbance. The second and most important component of the amnestic state is the anterograde amnesia, which indicates an inability to store, retain, and recall new knowledge. Patients with amnestic states cannot remember what they ate a few minutes ago or the details of an important event they may have experienced a few hours ago. In the acute stages, there also may be a tendency to fill in memory gaps with inaccurate, fabricated, and often implausible information. This is known as confabulation. Patients with the amnestic syndrome forget that they forget and tend to deny the existence of a memory problem when questioned.

CLINICAL EXAMINATION

A patient with an amnestic state is almost always disoriented, especially to time. Accurate temporal orientation and accurate knowledge of current news rule out a major amnestic state. The anterograde component of an amnestic state can be tested with a list of four to five words read aloud by the examiner up to five times or until the patient can immediately repeat the entire list without an intervening delay. In the next phase of testing, the patient is allowed to concentrate on the words and rehearse them internally for 1 min before being asked to recall them. Accurate performance in this phase indicates that the patient is motivated and sufficiently attentive to hold the words online for at least 1 min. The final phase of the testing involves a retention period of 5 to 10 min during which the patient is engaged in other tasks. Adequate recall at the end of this interval requires offline storage, retention, and retrieval. Amnestic patients fail this phase of the task and may even forget that they were given a list of words to remember. Accurate recognition of the words by multiple choice in a patient who cannot recall them indicates a less severe memory disturbance that affects mostly the retrieval stage of memory. The retrograde component of an amnesia can be assessed with questions related to autobiographical or historic events. The anterograde component of amnestic states is usually much more prominent than the retrograde component. In rare instances, usually associated with temporal lobe epilepsy or benzodiazepine intake, the retrograde component may dominate.

The assessment of memory can be quite challenging. Bedside evaluations may detect only the most severe impairments. Less severe memory impairments, as in the case of patients with temporal lobe epilepsy, mild head injury, or early dementia, require quantitative evaluations by neuropsychologists. Confusional states caused by toxic-metabolic encephalopathies and some types of frontal lobe damage interfere with attentional capacity and lead to secondary memory impairments, even in the absence of any limbic lesions. This sort of memory impairment can be differentiated from the amnestic state by the presence of additional impairments in the attention-related tasks described in the section on the frontal lobes.

CAUSES, INCLUDING ALZHEIMER’S DISEASE

Many neurologic diseases can give rise to an amnestic state. They include tumors (of the sphenoid wing, posterior corpus callosum, thalamus, or medial temporal lobe), infarctions (in the territories of the anterior or posterior cerebral arteries), head trauma, herpes simplex encephalitis, Wernicke-Korsakoff encephalopathy, paraneoplastic limbic encephalitis, and degenerative dementias such as Alzheimer’s disease and Pick’s disease. The one common denominator of all these diseases is the presence of bilateral lesions within one or more components in the limbic network. Occasionally, unilateral left-sided hippocampal lesions can give rise to an amnestic state, but the memory disorder tends to be transient. Depending on the nature and distribution of the underlying neurologic disease, the patient also may have visual field deficits, eye movement limitations, or cerebellar findings.

Alzheimer’s disease (AD) and its prodromal state of mild cognitive impairment (MCI) are the most common causes of progressive memory impairments. Temporal disorientation and poor recall of recent conversations are early manifestations. The predilection of the entorhinal cortex and hippocampus for early neurofibrillary degeneration in the MCI-AD spectrum is responsible for the initially selective impairment of episodic memory. In time, a full amnestic state emerges, but usually with additional impairments in language, attention, and visuospatial skills as the neurofibrillary degeneration spreads to additional neocortical areas.

Transient global amnesia is a distinctive syndrome usually seen in late middle age. Patients become acutely disoriented and repeatedly ask who they are, where they are, and what they are doing. The spell is characterized by anterograde amnesia (inability to retain new information) and a retrograde amnesia for relatively recent events that occurred before the onset. The syndrome usually resolves within 24 to 48 h and is followed by the filling in of the period affected by the retrograde amnesia, although there is persistent loss of memory for the events that occurred during the ictus. Recurrences are noted in approximately 20% of patients. Migraine, temporal lobe seizures, and perfusion abnormalities in the posterior cerebral territory have been postulated as causes of transient global amnesia. The absence of associated neurologic findings occasionally may lead to the incorrect diagnosis of a psychiatric disorder.

THE PREFRONTAL NETWORK FOR ATTENTION AND BEHAVIOR

Approximately one-third of all the cerebral cortex in the human brain is situated in the frontal lobes. The frontal lobes can be subdivided into motor-premotor, dorsolateral prefrontal, medial prefrontal, and orbitofrontal components. The terms frontal lobe syndrome and prefrontal cortex refer only to the last three of these four components. These are the parts of the cerebral cortex that show the greatest phylogenetic expansion in primates, especially in humans. The dorsolateral prefrontal, medial prefrontal, and orbitofrontal areas, along with the subcortical structures with which they are interconnected (i.e., the head of the caudate and the dorsomedial nucleus of the thalamus), collectively make up a large-scale network that coordinates exceedingly complex aspects of human cognition and behavior.

The prefrontal network plays an important role in behaviors that require multitasking and the integration of thought with emotion. Its integrity appears important for the simultaneous awareness of context, options, consequences, relevance, and emotional impact that allows the formulation of adaptive inferences, decisions, and actions. Damage to this part of the brain impairs mental flexibility, reasoning, hypothesis formation, abstract thinking, foresight, judgment, the online (attentive) holding of information, and the ability to inhibit inappropriate responses. Cognitive operations impaired by prefrontal cortex lesions often are referred to as “executive functions.”

Even very large bilateral prefrontal lesions may leave all sensory, motor, and basic cognitive functions intact while leading to isolated but dramatic alterations of personality and behavior. The most common clinical manifestations of damage to the prefrontal network take the form of two relatively distinct syndromes. In the frontal abulic syndrome, the patient shows a loss of initiative, creativity, and curiosity and displays a pervasive emotional blandness and apathy. In the frontal disinhibition syndrome, the patient becomes socially disinhibited and shows severe impairments of judgment, insight, and foresight. The dissociation between intact intellectual function and a total lack of even rudimentary common sense is striking. Despite the preservation of all essential memory functions, the patient cannot learn from experience and continues to display inappropriate behaviors without appearing to feel emotional pain, guilt, or regret when those behaviors repeatedly lead to disastrous consequences. The impairments may emerge only in reallife situations when behavior is under minimal external control and may not be apparent within the structured environment of the medical office. Testing judgment by asking patients what they would do if they detected a fire in a theater or found a stamped and addressed envelope on the road is not very informative since patients who answer these questions wisely in the office may still act very foolishly in the more complex real-life setting. The physician must therefore be prepared to make a diagnosis of frontal lobe disease on the basis of historic information alone even when the mental state is quite intact in the office examination.

CLINICAL EXAMINATION

The emergence of developmentally primitive reflexes, also known as frontal release signs, such as grasping (elicited by stroking the palm) and sucking (elicited by stroking the lips) are seen primarily in patients with large structural lesions that extend into the premotor components of the frontal lobes or in the context of metabolic encephalopathies. The vast majority of patients with prefrontal lesions and frontal lobe behavioral syndromes do not display these reflexes.

Damage to the frontal lobe disrupts a variety of attention-related functions, including working memory (the transient online holding of information), concentration span, the scanning and retrieval of stored information, the inhibition of immediate but inappropriate responses, and mental flexibility. The capacity for focusing on a trend of thought and the ability to shift the focus of attention voluntarily from one thought or stimulus to another can become impaired. Digit span (which should be seven forward and five reverse) is decreased; the recitation of the months of the year in reverse order (which should take less than 15 s) is slowed; and the fluency in producing words starting with the letter a, f, or s that can be generated in 1 min (normally ≥ 12 per letter) is diminished even in nonaphasic patients. Characteristically, there is a progressive slowing of performance as the task proceeds; e.g., a patient asked to count backward by threes may say “100, 97, 94,…91,…88,” etc., and may not complete the task. In “go–no go” tasks (where the instruction is to raise the finger upon hearing one tap but keep it still upon hearing two taps), the patient shows a characteristic inability to keep still in response to the “no go” stimulus. Mental flexibility (tested by the ability to shift from one criterion to another in sorting or matching tasks) is impoverished; distractibility by irrelevant stimuli is increased; and there is a pronounced tendency for impersistence and perseveration.

These attentional deficits disrupt the orderly registration and retrieval of new information and lead to secondary memory deficits. Those memory deficits can be differentiated from the primary memory impairments of the amnestic state by showing that they improve when the attentional load of the task is decreased. Working memory (also known as immediate memory) is an attentional function based on the temporary online holding of information. It is closely associated with the integrity of the prefrontal network and the ascending reticular activating system. Retentive memory, in contrast, depends on the stable (offline) storage of information and is associated with the integrity of the limbic network. The distinction of the underlying neural mechanisms is illustrated by the observation that severely amnestic patients who cannot remember events that occurred a few minutes ago may have intact if not superior working memory capacity as shown in tests of digit span.

CAUSES: TRAUMA, NEOPLASM, AND FRONTOTEMPORAL DEMENTIA

The abulic syndrome tends to be associated with damage in dorsal prefrontal cortex, and the disinhibition syndrome with damage in ventral prefrontal cortex. These syndromes tend to arise almost exclusively after bilateral lesions. Unilateral lesions confined to the prefrontal cortex may remain silent until the pathology spreads to the other side; this explains why thromboembolic CVA is an unusual cause of the frontal lobe syndrome. Common settings for frontal lobe syndromes include head trauma, ruptured aneurysms, hydrocephalus, tumors (including metastases, glioblastoma, and falx or olfactory groove meningiomas), and focal degenerative diseases. A major clinical form of FTLD known as the behavioral variant of frontotemporal dementia (bvFTD) causes a progressive frontal lobe syndrome that can start as early as the fifth decade of life. In these patients, the anterior temporal lobe and caudate nucleus are also atrophic. The behavioral changes can include shoplifting, compulsive gambling, sexual indiscretions, and obsessive-compulsive preoccupations, arising on a background of indifference. In many patients with Alzheimer’s disease, neurofibrillary degeneration eventually spreads to prefrontal cortex and gives rise to components of the frontal lobe syndrome, but almost always on a background of severe memory impairment.

Lesions in the caudate nucleus or in the dorsomedial nucleus of the thalamus (subcortical components of the prefrontal network) also can produce a frontal lobe syndrome. This is one reason why the changes in mental state associated with degenerative basal ganglia diseases such as Parkinson’s disease and Huntington’s disease may take the form of a frontal lobe syndrome. Because of its widespread connections with other regions of association cortex, one essential computational role of the prefrontal network is to function as an integrator, or “orchestrator,” for other networks. Bilateral multifocal lesions of the cerebral hemispheres, none of which are individually large enough to cause specific cognitive deficits such as aphasia and neglect, can collectively interfere with the connectivity and integrating function of the prefrontal cortex. A frontal lobe syndrome is the single most common behavioral profile associated with a variety of bilateral multifocal brain diseases, including metabolic encephalopathy, multiple sclerosis, and vitamin B12 deficiency, among others. Many patients with the clinical diagnosis of a frontal lobe syndrome tend to have lesions that do not involve prefrontal cortex but involve either the subcortical components of the prefrontal network or its connections with other parts of the brain. To avoid making a diagnosis of “frontal lobe syndrome” in a patient with no evidence of frontal cortex disease, it is advisable to use the diagnostic term frontal network syndrome, with the understanding that the responsible lesions can lie anywhere within this distributed network.

A patient with frontal lobe disease raises potential dilemmas in differential diagnosis: the abulia and blandness may be misinterpreted as depression, and the disinhibition as idiopathic mania or acting out. Appropriate intervention may be delayed while a treatable tumor keeps expanding. An informed approach to frontal lobe disease and its behavioral manifestations may help prevent such errors.

CARING FOR PATIENTS WITH DEFICITS OF HIGHER CEREBRAL FUNCTION

Some of the deficits described in this chapter are so complex that they may bewilder not only the patient and family but also the physician. It is imperative to carry out a systematic clinical evaluation to characterize the nature of the deficits and explain them in lay terms to the patient and family. Such an explanation can allay at least some of the anxieties, address the mistaken impression that the deficit (e.g., social disinhibition or inability to recognize family members) is psychologically motivated, and lead to practical suggestions for daily living activities. The consultation of a skilled neuropsychologist may aid in the formulation of diagnosis and management. Patients with simultanagnosia, for example, may benefit from the counterintuitive instruction to stand back when they cannot find an item so that a greater search area falls within the immediate field of gaze. Some patients with frontal lobe disease can be extremely irritable and abusive to spouses yet display all the appropriate social graces during a visit to the medical office. In such cases, the history may be more important than the bedside examination in charting a course of treatment.

Reactive depression is common in patients with higher cerebral dysfunction and should be treated. These patients may be overly sensitive to the usual doses of anti-depressants or anxiolytics and require a careful titration of dosage. Brain damage may cause a dissociation between feeling states and their expression so that a patient who may superficially appear jocular could still be suffering from an underlying depression that needs to be treated. In many cases, agitation may be controlled with reassurance. In other cases, treatment with benzodiazepines, antiepilectics, or sedating antidepressants may become necessary. If neuroleptics become absolutely necessary for the control of agitation, atypical neuroleptics are preferable because of their lower extrapyramidal side effects. Treatment with neuroleptics in elderly patients with dementia requires weighing the potential benefits against the potentially serious side effects.

Spontaneous improvement of cognitive deficits due to acute neurologic lesions is common. It is most rapid in the first few weeks but may continue for up to 2 years, especially in young individuals with single brain lesions. The mechanisms for this recovery are incompletely understood. Some of the initial deficits appear to arise from remote dysfunction (diaschisis) in parts of the brain that are interconnected with the site of initial injury. Improvement in these patients may reflect, at least in part, a normalization of the remote dysfunction. Other mechanisms may involve functional reorganization in surviving neurons adjacent to the injury or the compensatory use of homologous structures, e.g., the right superior temporal gyrus with recovery from Wernicke’s aphasia. In some patients with large lesions involving Broca’s and Wernicke’s areas, only Wernicke’s area may show contralateral compensatory reorganization (or bilateral functionality), giving rise to a situation in which a lesion that should have caused a global aphasia becomes associated with a residual Broca’s aphasia. Prognosis for recovery from aphasia is best when Wernicke’s area is spared. Cognitive rehabilitation procedures have been used in the treatment of higher cortical deficits. There are few controlled studies, but some show a benefit of rehabilitation in the recovery from hemispatial neglect and aphasia. Some types of deficits may be more prone to recovery than others. For example, patients with CVA and nonfluent aphasias are more likely to benefit from speech therapy than are patients with fluent aphasias and comprehension deficits. In general, lesions that lead to a denial of illness (e.g., anosognosia) are associated with cognitive deficits that are more resistant to rehabilitation. Periodic neuro-psychological assessment is necessary for quantifying the pace of the improvement (or of the progression in the case of dementias) and for generating specific recommendations for cognitive rehabilitation, modifications in the home environment, the timetable for returning to work in patients recovering from acute lesions, and the scheduling of retirement or disability status in patients with degenerative diseases. Determining driving competence is challenging, especially in the early stages of dementing diseases. The diagnosis of a neurodegenerative disease is not by itself sufficient for asking the patient to stop driving. An on-the-road driving test and reports from family members may help time decisions related to this very important activity.

There is a mistaken belief that dementias are anatomically diffuse and that they cause global cognitive impairments. This is true only at the terminal stages. During most of the clinical course, dementias are exquisitely selective with respect to anatomy and cognitive pattern. Alzheimer’s disease, for example, causes the greatest destruction in medial temporal areas belonging to the memory network and is clinically characterized by a correspondingly severe amnesia. There are other dementias in which memory is intact. Selective degeneration of the frontal lobes in FTLD leads to a gradual dissolution of behavior and executive functions. Primary progressive aphasia is characterized by a gradual atrophy of the left perisylvian language network and a selective dissolution of language that can remain isolated for up to 10 years. An enlightened approach to the differential diagnosis and to the individualized care of patients with acute and progressive damage to the cerebral cortex requires an understanding of the principles that link neural networks to higher cerebral functions.